The 1821 opera Der Freichütz (the Freeshooter), by Weber, is considered the first romantic German opera. Much of its plot is focused on the production and use of magic bullets which, when fired, unerringly hit their target. The young forester, Max, is taking part in a shooting competition in order to win the hand of his love, Agathe. He is persuaded, somewhat against his better judgement, to cast seven magic bullets – invoking the help of Samiel, the Black Huntsman. The consequences of this action are predictably disastrous.
Some years later Paul Ehrlich used the term magic bullets (Zauberkugel), presumably inspired by the opera, or the folklore behind it, to describe antibodies. In English he described them first as charmed bullets, and was quoted as comparing antibodies to “magic bullets, constrained by a charm to fly straight to their specific objective, and to turn aside from anything else in their path” – somewhat like heat-seeking missiles. This metaphor was a powerful one and encouraged scientists and doctors to develop antibodies for treating disease. But it is also a bad metaphor that has led to confusion about how antibodies work and led some researchers astray.
At the time that Ehrlich coined this phrase he was interested in understanding the use of antibodies in natural immunity, and there was considerable interest in the development of antibodies as therapeutic agents (Emil Behring had just won the Nobel Prize for developing antisera – blood serums containing antibodies – for treating diphtheria). Ehrlich’s thinking of antibodies as magic bullets anticipated both the modern use of monoclonal antibodies – drugs that contain copies of antibodies made by the body – and the use of antibodies linked to drugs to target toxic agents at cancer cells.
Lulled by poetic power
The term magic bullet has poetic power, and has motivated people to develop antibodies for treatment. And it has been used by many (including myself) in papers and grant applications. Yet in one important sense it is misleading and has led to confusion. People can be lulled into thinking of antibodies as being able to seek out or home in on their target. But antibodies actually have no way of knowing where their target is, and they have no way of deliberately moving towards it.
I would suggest that rather than “magic bullets”, a more apt metaphor for antibodies would be “sticky drunkards”. When you inject antibodies into a patient they simply circulate through the blood stream and diffuse through the body, and it is only if they bump into their target antigen that they stick to it.
This is like releasing billions of drunk people from a bar into a city late at night. These drunkards stumble and walk in random directions. But the drunkards are specifically sticky to lamp-posts. So they blunder around until they randomly bump into a lamp-post, at which point they cling on to it.
So if you were to look at the city you would at first see the drunkards disgorging from the bar, and then slowly spreading out in a random way through the city (possibly moving faster along transportation routes). Then you will start to see some of them attach themselves to lamp-posts. If you wait long enough (and if there are enough lamp-posts), you may eventually see that all of the drunkards are hanging onto a lamp-post, at least until they randomly lose their grip and stagger off ready to bump into the next one.
These sticky drunkards do specifically target lamp-posts, but they do so by being specifically sticky, not by knowing where the lamp-posts are and seeking them out. This is different to a magic bullet, which seeks out its target.
Ehrlich would have understood this concept, if not the language. Most of his experimental work was based on modification of dyes with toxic substances, with the idea that dyes could stain specific structures or cells and so could provide specificity to the poisonous agent. His greatest success was Salvarsan, an arsenic-containing compound that was the first effective treatment for syphilis.
A dye or stain works in a similar manner to the sticky drunkards – you immerse your tissue in the compound which then diffuses. It then sticks to the structures that it is specific for. Washing is then used to remove any unstuck dye. The result is specific staining, but not as a result of the dye homing in on its target.
The misleading nature of the magic bullet metaphor has importance. In my experience, many students of immunology instinctively think that an antibody injected into a patient will home in on the tumour. This is reinforced by animations of the immune system that invariably show antibodies moving purposefully towards their targets. This makes people think that they can use small amounts of antibody to attack the target cell (after all you only need one magic bullet), and that the antibody will rapidly head for its target (a bullet does not take long). But if you think of sticky drunkards then you realise that the best way to ensure hitting your target is to have as many drunkards as possible, and give them the most time possible to blunder around.
There was a catch to the magic bullets in Der Freichütz, however. Seven bullets were cast in the opera. Six of them hit the shooter’s target, but the seventh was under the control of the evil one. When Max fires the seventh, it flies at his fiancé, Agathe. So the magic bullet – while not the best metaphor – is at least a reminder that antibodies can also have unwanted, off-target effects.